Pharmaceutical formulation for the treatment of osteoarthritis containing clodronic acid and hyaluronic acid

ABSTRACT

Disclosed are pharmaceutical compositions containing clodronic acid and hyaluronic acid or their salts as active constituents, mixed with suitable vehicles.

This invention relates to pharmaceutical formulations containing hyaluronic acid and clodronic acid or their salts, especially their sodium salts, as active constituents.

Osteoarthritis (OA) is a progressive chronic illness which particularly affects the joints most subject to mechanical stresses, such as the hips and knees. When this condition arises, the whole joint is affected by a series of degradation and repair processes which eventually alter the anatomy and function of the joint, affecting all the joint components such as the cartilage, subchondral bone and synovial tissues. OA is therefore the result of a set of interrelations between systemic factors (e.g. advanced age or obesity) and local factors (e.g. trauma or excessive use) which are modulated in turn by numerous predisposing factors, possibly combined with infectious and inflammatory events with various aetiologies. In the past, the cartilage was considered to be responsible for OA, and its only target. However, extensive evidence has recently been obtained that the subchondral bone may be the pathogenetic factor responsible for the onset and progress of OA.

In this complex of events, attempts have been made over the years to treat the condition by combating the individual causal processes and using local or systemic anti-inflammatory drugs or intra-articular injections of hyaluronic acid. More recently, the use of drugs which affect the bone metabolism, such as bisphosphonates, has been suggested. Limited use has also been made of some drugs described, more or less arbitrarily, as chondroprotectors (anthraquinones, chondroitin sulphate, etc.), but their real curative capacity is very low and controversial.

In particular, bisphosphonates are well known substances for inhibiting bone resorption and are used in the treatment of postmenopausal osteoporosis, Paget's disease, and tumour osteolysis.

Nevertheless, in a study on rats conducted by the Applicant, sodium clodronate, which belongs to the category of bisphosphonates, proved able to inhibit damaging effects on the joint structures by Freund's adjuvant, which suggests a possible use in joint disease, especially gonarthritis and coxarthritis, in view of its effects on the inflammatory cytokines, its inhibiting effect on the macrophages and the production of metalloproteases, and its stabilising effect on the subchondral bone. In another study on patients with synovitis secondary to knee osteoarthritis, clodronate treatment determined a significant improvement of patient's symptomatology (R. Cocco et al.—, J. Biol. Res., 1999 September N. 11-12—Vol LXXV) suggesting a possible role of bisphosphonate in the treatment of osteoarthritis.

EP 0203649 discloses the use of clodronic acid at the concentration from 10⁻¹ to 10⁻⁶ M for the preparation of a medicament to be administered intra-articularly for the treatment of osteoarthritis.

During a clinical trial performed by the Applicant with a bisphosphonate (sodium clodronate) for intra-articular use in patients suffering from evident gonarthritis, interesting results were observed after 5 intra-articular injections of 2 mg of sodium clodronate in terms of attenuation of pain and recovery of joint movement.

Furthermore, during an official multicenter clinical study sponsored by the Applicant to assess the effectiveness of intra-articular administration of clodronate in patients affected by gonalgia and gonarthrosis, the best responses were obtained after intra-articular injection of 2 mg of clodronate supplied once a week over 4 consecutive weeks.

However, in addition to these favourable results, some adverse events were also observed, such as a pain response at the time of the injection due to the excessive acidity of the clodronate solution. The low pH used was dictated by stability problems, +which made less acid values of the solutions unacceptable.

Another important product used for OA is hyaluronic acid in its various forms with different molecular weights. Hyaluronan products include Hyalgan® (sodium hyaluronate, molecular weight [MW] 500-730 kDa), Supartz® (sodium hyaluronate, MW 630-1170 kDa), Artz® (sodium hyaluronate, MW 700-1,200 kDa) and others of higher molecular weight (MW from 1100 to 6000 kDa) such as Orthovisc® (MW 1100-2900), Nuflexxa® (MW 2400-3500 kDa) and Synvisc® (hylan G-F 20, approx MW 6000 kDa).

Sodium hyaluronate (MW 500-730 kDa) is administered as three or five weekly 2 ml, 10 mg/ml injections (Hyalgan—Prescribing Information. NY Sanofi-Synthelabo Inc. 2001); similarly sodium hyaluronate (MW 630-1170 kDa; 700-1200 kDa) is administered as a weekly 2.5 ml, 10 mg/ml injection for 5 weeks (Supartz—package insert; Seikagaku Corporation 2001; Artz—Prescribing Information) and higher molecular weight hyaluronans are employed as at least three to five weekly 2 ml, from 8 to 25 mg/ml (M. Pagnano, G. Westrich; Osteoarthritis and Cartilage (2005), 13, 751-761; L. Stefan et al. Ann Rheum Dis, 1996, 55:424-431).

The intra-articular application of hyaluronic acid involves not only some interference with the synovial cells, but also a mechanical effect of lubrication of the cartilage structures. Its efficacy in the relief of pain and improvement in joint function has been shown in numerous clinical studies.

However, it was observed that oligosaccharide fragments of hyaluronic acid deriving from the degradation activity of the endogenous enzyme hyaluronidase also possess an angiogenetic action as well as stimulating the production of proinflammatory cytokines (TNFα and IL-1β) by the macrophages (M. Fiorini et al.—, Rivista Italiana di Tissue Banking 51-52; D. C West et al.—, Science 1985, 228:1324-1326; A. Sattar et al.—J. Invest Dermatol, 1994, 103:576-9), events which can occur after the intra-articular application of hyaluronic acid and that can certainly be harmful to a cartilage if not suitably counteracted.

In practice, despite some favourable effects found with the clinical use of hyaluronic acid, it does not intervene in the degenerative processes affecting the subchondral bone and it has been found eventually cause inflammation and cartilage damage, (C. Bernardeauc et al.—Ann Rheum Dis 2001, 60:518-520; M P Puttick et al.—, J Rheumatol. 1995 July; 22(7):1311-4; D. Magilavy et al.—, J. Bone Joint Surg. Am. 2003 85(5):967-969) especially in long-term and/or repeated courses of treatment (A. Roth et al.—, Arthritis Research and Therapy 2005, 7:R677-R686; Seth S. et al.—, J. Bone Joint. Am., 2002 September 84(9):1619-1623).

Moreover, for hyaluronic acid to perform its protective action, repeated i.a. administrations (at least 3, but more frequently 5 or more injections at short intervals) are required, obviously resulting in low compliance by patients and the risk of problems associated with this practice, which is not easy to perform.

It has now surprisingly been found that a solution of sodium clodronate in hyaluronic acid, at low concentrations, gives better results in a shorter time than the individual products. The formulations according to the invention have also enabled lower concentrations of sodium clodronate than usual to be used, thus reducing the side effects associated with the acidity of the compound and advantageously reducing the number of administrations. At the same time, sodium clodronate, thanks to its pharmacological properties, counteracts any adverse effects of i.a. administration of hyaluronic acid as a consequence of the angiogenetic and stimulatory activity of the macrophagic production of cytokines induced by oligosaccharide fragments of HA, and also allows a reduction in the number of hyaluronic acid administrations. Furthermore, in case of serious OA which necessarily requires high clodronate concentration, the present formulation, thanks to the buffered and masking effect of hyaluronic acid, permits the administration of clodronate thus reducing the pain commonly related to intra-articular administration. The formulations of invention therefore surprisingly represent a new improved solution for the treatment of OA which is particularly advantageous in terms of efficacy, compliance and reduction of adverse effects compared with the prior art.

Thus, the object of the present invention is a pharmaceutical composition comprising clodronic acid and hyaluronic acid or their salts as active ingredients.

The sodium clodronate concentration can range between 0.5 mg and approx. 1.5-2.0 mg. The preferred concentration is 1 mg/ampoule in 1 or 2 ml of hyaluronic acid. Higher doses of clodronate (approx 3-5 mg) can be used, provided that they are suitably buffered with appropriate amounts of hyaluronic acid. Said amounts can reasonably range between 5 and 30 mg/ampoule and final volumes of between 0.5 and 5.0 ml, to be used according to the joint affected.

Hyaluronic acid in all its different forms with different molecular weights (MW from 0.4×10³ kDa to approx 6×10³ kDa) as known from the present prior art or which could be developed in the future can be used to perform the present invention. Preferred hyaluronic acids or sodium salt thereof are those with a molecular weight (MW) of between 0.4 and 1.5×10³ kDa.

Sodium clodronate and sodium hyaluronan solutions generally have a pH of between 4.8 and 6.0.

A preferred solution of the invention consists in a composition of 1 mg of sodium clodronate in 1 or 2 ml of hyaluronic acid sodium salt, with a molecular weight of approx 0.6×10³ kDa (10-20 mg).

A further preferred solution of the invention consists in a composition of 3 mg of sodium clodronate in 2-3 ml of hyaluronic acid sodium salt, with a molecular weight of approx 0.9×10³ kDa (25 mg).

The compositions according to the invention may contain the usual preservatives, especially for the formulation of the combined product in disposable syringes.

Preliminary clinical trials with the formulations according to the invention were based on the measurement of Womac 20 and Womac 50, ie. a 20% and 50% improvement in the symptoms to establish the responders to the treatment (Ann Rheum Dis. 2005). Recently, to assess the effectiveness of intra-articular clodronic acid, 1 mg of clodronic acid is administered in patients with gonarthritis obtaining an improvement in symptoms which, when evaluated with Womac 50, related to 32% of the patients.

The invention is illustrated in more detail in the following example.

EXAMPLE

15 patients suffering from gonarthritis received, according to the invention, an infiltration of 2 ml of solution constituted by 20 mg of hyaluronic acid (Hyalgan) together with 1 mg of clodronic acid once a week for 3 weeks.

At the end of the infiltration cycle, as reassumed in the following table, 58% of the patients were responders according to Womac 20, and 37% were responders according to Womac 50.

These results were better than the equivalent infiltration cycle performed with the individual drugs; Womac 20 was 41% and 43% and Womac 50 was 24% and 27% for hyaluronic acid (20 mg/2 ml) and clodronic acid respectively (1 mg in 2 ml of buffered placebo solution).

The final result of 3 weekly infiltrations of the combination of the two drugs was also better than the cycle with 5 weekly infiltrations of hyaluronic acid (Womac 20: 51% and Womac 50: 30%) or clodronic acid (Womac 20: 54% and Womac 50: 32%).

TABLE Treatment volume of the total quantity of drug at end Womac Womac type time injected solution of treatment 50 20 Sodium hyaluronate (20 mg) + once a week 2 ml sodium hyaluronate: 60 mg 37 58 clodronic acid (1 mg) for 3 week clodronic acid: 3 mg Sodium hyaluronate (20 mg) once a week 2 ml sodium hyaluronate: 60 mg 24 41 for 3 week Clodronic acid (1 mg) once a week 2 ml clodronic acid: 3 mg 27 43 for 3 week Sodium hyaluronate (20 mg) once a week 2 ml sodium hyaluronate: 100 mg 30 51 for 5 week Clodronic acid (1 mg) once a week 2 ml 5 mg 32 54 for 5 week

The invention therefore improved efficacy as measured by both Womac 20 and Womac 50.

This finding is particularly surprising in view of the fact that not only the composition of the present invention resolves the symptomatology of a major number of patients, but three weekly administrations are enough to give better results than cycles of five weekly infiltrations of the two substances administered separately. Thus, the composition of the invention resolves the patient's symptomatology also in a shorter time than the two active principles given separately.

Furthermore, in reference to the cycle with 5 weekly infiltrations of hyaluronic acid or clodronic acid administered separately, it should be considered that the composition of the invention gives better response in term of time and number of responders by means a total reduced quantity of each single drug (60 mg of sodium hyaluronate towards 100 mg of the same, and 3 mg of clodronic acid towards 5 mg of the same).

Moreover, the tolerability of the combined treatment was excellent; in particular, no cases of acute microcrystalline arthritis or knee pain were observed in the hours following the injection.

Regard the efficacy and the tolerability of the composition of the invention, in another experimental analysis two patients suffering from severe gonarthritis, as assessed by radiological analysis, received an infiltration of a high clodronic acid concentration (3 mg) together with sodium hyaluronate (Artz) 25 mg/2.5 ml. The patients reported a reduced symptomatology in terms of VAS (pain visual analogue scale; Elsevier 1984—Oxford University Press; 1989) 7 days after the treatment, and also no pain response at the time of the injection which instead normally occurs when clodronate alone is administered intra-articularly, especially at high concentration. Thus, the composition of the invention, thanks to the presence of hyaluronic acid, also allows to administer high concentration of clodronate in patients in need thereof.

Therefore, the composition of the present invention represents an improved solution in terms of efficacy and compliance for the treatment of osteoarthritis (OA). Furthermore, it constitutes a new possible approach of treatment especially for those patients in which separate treatments failed. 

1-17. (canceled)
 18. A pharmaceutical composition comprising clodronic acid and hyaluronic acid or their salts as active constituents, mixed with suitable vehicles, and having a pH of between 4.8 and 6.0.
 19. The composition as claimed in claim 18, comprising from 0.5 to 5 mg of clodronic acid or its salts.
 20. The composition as claimed in claim 18, comprising sodium clodronate.
 21. The composition as claimed in claim 18, comprising from 10 to 30 mg to hyaluronic acid or its salts.
 22. The composition as claimed in claim 18, comprising hyaluronic acid or its salts having a molecular weight from 0.4×10³ to 6×10³ kDa.
 23. The composition as claimed in claim 22, comprising hyaluronic acid or its salts having a molecular weight from 0.4×10³ to 1.5×10³ kDa.
 24. The composition as claimed in claim 21, comprising sodium hyaluronate.
 25. The composition as claimed in claim 18, comprising sodium clodronate and sodium hyaluronate.
 26. The composition as claimed in claim 18, which is suitable for the intra-articular administration.
 27. The composition as claimed in claim 18, in the form of disposable syringes.
 28. A method of treating osteoarthritis comprising administering by intra-articular route an effective amount of a combination of clodronic acid and hyaluronic acid or their salts at a pH of between 4.8 and 6.0 to a subject in need thereof.
 29. The method as claimed in claim 28 wherein the clodronic acid is in the form of sodium clodronate.
 30. The method as claimed in claim 28, wherein the hyaluronic acid is in the form of sodium hyaluronate 